As we enter into an era of personalized medicine, it becomes increasingly important to define the factors that confer disease risk and outcome. Since these determinants cannot be easily controlled in human epidemiological studies, genetically-engineered mouse (GEM) strains provide mechanistically-tractable platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools and treatments. Pediatric low-grade brain tumors (gliomas) represent one such challenging disease with respect to predicting clinical progression, optimizing treatment, and improving neurologic outcome. In the most common inherited cause for pediatric low-grade glioma, neurofibromatosis type 1 (NF1), 15-20% of children develop optic pathway gliomas (OPGs), leading to visual decline in 30-60% of affected individuals. Moreover, conventional chemotherapy results in disease stabilization in only 50-60% of children, and few experience improvement in their visual acuity following treatment. Currently, it is not possible to predict which child with a NF1-OPG will experience visual dysfunction (Barrier 1) and what treatments are most likely to result in tumor response and lead to visual recovery (Barrier 2). Over the past 10 years, as part of the National Cancer Institute Mouse Models of Human Cancers Consortium, we leveraged a collection of novel Nf1 GEM strains with optic glioma to establish that (1) the germline NF1 gene mutation partly determines NF1 protein expression and function, (2) female, but not male, Nf1 mutant mice with optic glioma have reduced visual acuity, (3) non-neoplastic immune system-like cells (microglia) carrying only a germline NF1 gene mutation are required for murine optic glioma formation and growth, and (4) murine optic gliomas contain glioma stem cells (optic GSCs) with unique, and potentially targetable, molecular and cellular properties. Based on these findings, we propose a systematic, team-based dissection of the factors responsible for NF1-optic glioma progression, vision loss, and therapeutic success. For this initiative, we have assembled a cross- disciplinary collaborative team to (a) define the molecular etiology for female susceptibility to OPG-induced visual decline (Aim 1), (b) assess the impact of the germline NF1 gene mutation on OPG-induced visual decline (Aim 2) as well as (c) microglia function relevant to potential stroma-directed glioma treatments (Aim 3), and (d) exploit a series of distinct GSCs from Nf1 optic glioma GEMs for developing new treatments that uniquely target the cells most responsible for maintaining the tumor (Aim 4). Collectively, these studies have immediate translatability to the human condition, given the wide clinical availability of NF1 genetic testing, recent advances in rapid cellular reprograming, and the existence of two large international consortia with proven expertise in NF1-OPG clinical assessment and therapeutic evaluation.